There are currently no approved therapies for Multiple Sclerosis (MS) that promote remyelination and axon preservation. MS is a chronic immune-mediated disease of the central nervous system (CNS) characterized by demyelinating white matter lesions, glial scar formation and axonal loss. Thyroid hormones (THs) play a critical role in developmental myelination, however their role in remyelination has not yet been clearly defined. During developmental myelination THs act through nuclear hormone receptors to promote oligodendrocyte maturation and myelination. Recent studies in rodent models of demyelination suggest that THs have the capacity to promote remyelination, however non-specific stimulation of TH receptors can also produce significant undesirable side-effects. In this research project, we will investigate if a thyroid hormone receptor selective thyromimetic, GC-1, can promote recovery in the cuprizone model of demyelination. We will also investigate whether oligodendrocyte progenitor cells (OPCs) in the healthy adult brain are sensitive to exogenous TH administration, an effect that could lead to aberrant OL differentiation, or if they only become reactive following injurious events, such as demyelination. There are two major TH receptors (TRs). TR is predominantly expressed in the heart and is responsible for the known cardiac effects of THs, whereas TR is predominantly expressed in the liver and is involved in lipid regulation. Both TR and TR are expressed in the CNS and are known to modulate myelination during development. Despite unequivocal evidence of the important role played by TH in myelination, we do not yet clearly understand which TRs are required to mediate these effects. We have preliminary data showing that GC-1, a TR selective agonist, can induce differentiation of OPCs into myelin forming oligodendrocytes in vitro. We also find that TR expression increases in vivo during remyelination in the cuprizone model of demyelination. We now propose to test the hypothesis that selective agonism of the thyroid hormone receptor by GC-1 can enhance remyelination following a demyelinating insult in vivo. In aim 1 we will investigate the potential for GC-1 to enhance remyelination in both acute and chronic demyelination scenarios. In aim 2 we will explore the mechanisms by which thyroid hormones and their receptors regulate OPC differentiation in both the healthy adult brain and in the remyelinating state. We hypothesize that in the adult CNS TR expression is one mechanism by which OPC differentiation is tightly regulated, whereas during remyelination TR is up-regulated as part of the endogenous recovery process. The results of the proposed experiments could provide strong preclinical rationale for the further clinical translation of GC-1 in MS.